Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibilitygene for bipolar disorder

Bipolar affective disorder is a genetically complex psychiatric disorder wi th a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a domina nt skin disorder with a neuropsychiatric component. The gene for Darier's d isease was mapped to chromosome 12q23-q24.1 and linkage studies by us and o thers have subsequently implicated this region as harbouring a susceptibili ty gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a p otential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this h ypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random cl ustering of missense mutations in A TP2A2 in neuropsychiatric Darier patien ts, and functional data demonstrating the role of SERCA2 in intracellular c alcium regulation. In a panel of 15 unrelated bipolar patients from multipl y affected families showing increased allele sharing at markers in the 12q2 3-q24.1 region, we performed mutational screening of the ATP2A2 coding sequ ence, promoter regions, and 3' untranslated region and identified six seque nce variations. These were analysed in a large sample of bipolar patients ( n = 324) and control subjects (n = 327). Analysis of allele and genotype di stributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipol ar disorder.